RESUMO

Macrophage migration inhibitory factor (MIF) is present in high amounts in the BALF and serum of asthmatic patients, contributing to the pathogenesis of experimental asthma induced by OVA in mice. Whether MIF contributes to the physiopathology on a more complex and relevant asthma model has not been characterized. Mif-deficient (Mif-/- ) or WT mice treated with anti-MIF antibody were challenged multiple times using house dust mite (HDM) extract by the intranasal route. HDM-challenged Mif-/- mice presented decreased airway hyperresponsiveness, lung infiltration of eosinophils, mucus hypersecretion, and subepithelial fibrosis compared to HDM-challenged WT mice. Amounts of IL-4, IL-5, and IL-13 were decreased in the lungs of Mif-/- mice upon HDM challenges, but the increase of CCL11 was preserved, compared to HDM-challenged WT mice. We also observed increased numbers of group 2 innate lymphoid cells and Th2 cells in the BALF and mediastinal LNs (mLN)-induced challenged by HDM of WT mice, but not in HDM-challenged Mif-/- mice. Anti-MIF treatment abrogated the airway infiltration of eosinophils, mucus hypersecretion, and subepithelial fibrosis in the lungs of HDM-challenged mice. In conclusion, MIF ablation prevents the pathologic hallmarks of asthma in HDM-challenged mice, reinforcing the promising target of MIF for asthma therapy.

Assuntos

Asma , Fatores Inibidores da Migração de Macrófagos , Animais , Camundongos , Pyroglyphidae , Fatores Inibidores da Migração de Macrófagos/genética , Imunidade Inata , Linfócitos/patologia , Pulmão , Inflamação/patologia , Fibrose

RESUMO

Microbe-host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.

Assuntos

Colite Ulcerativa , Doença de Crohn , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Disbiose , Microbioma Gastrointestinal/fisiologia , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/terapia

RESUMO

Phenolic compounds (PCs) present in foods are associated with a decreased risk of developing inflammatory diseases. The aim of this study was to extract and characterize PCs from craft beer powder and evaluate their potential benefits in an experimental model of inflammatory bowel disease (IBD). PCs were extracted and quantified from pure beer samples. BALB/c mice received either the beer phenolic extract (BPE) or beer powder fortified with phenolic extract (BPFPE) of PCs daily for 20 days by gavage. Colon samples were collected for histopathological and immunohistochemical analyses. Dextran sodium sulfate (DSS)-induced mice lost more weight, had reduced colon length, and developed more inflammatory changes compared with DSS-induced mice treated with either BPE or BPFPE. In addition, in DSS-induced mice, the densities of CD4- and CD11b-positive cells, apoptotic rates, and activation of NF-κB and p-ERK1/2 MAPK intracellular signaling pathways were higher in those treated with BPE and BPFPE than in those not treated. Pretreatment with the phenolic extract and BPFPE remarkably attenuated DSS-induced colitis. The protective effect of PCs supports further investigation and development of therapies for human IBD.

Assuntos

Cerveja , Colite , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Colite/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pós , Dodecilsulfato de Sódio/toxicidade

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related death in the world. The aim of this study was to investigate the geographic distribution and time trends of CRC in Brazil. METHODS: Data were retrospectively retrieved from January 2005 to December 2018 from the Brazilian Public Health System. The incidence and lethality rates of CRC per 100,000 inhabitants in each municipality were estimated from hospitalizations and in-hospital deaths and were classified by age, sex, and demographic features. RESULTS: During the study period, the mean incidence of CRC estimated from hospitalizations and adjusted to available hospital beds more than tripled from 14.6 to 51.4 per 100,000 inhabitants (352%). Increases in CRC incidence were detected in all age ranges, particularly among people aged 50-69 years (266%). Incidence rates increased in all 5 macroregions, with a clear South to North gradient. The greatest changes in incidence and lethality rates were registered in small-sized municipalities. CRC lethality estimated from in-hospital deaths decreased similarly in both sexes, from 12 to 8% for males and females, from 2005 to 2018. The decline in lethality rates was seen in all age ranges, mainly in people aged 50 to 69 years (- 38%). CONCLUSIONS: CRC incidence is increasing, predominantly above fifty years of age, and also in areas previously considered as having low incidence, but the increase is not paralleled by lethality rates. This suggests recent improvements in CRC screening programs and treatment, but also supports the spread of environmental risk factors throughout the country.

Assuntos

Neoplasias Colorretais , Hospitalização , Idoso , Brasil/epidemiologia , Neoplasias Colorretais/epidemiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos

RESUMO

Neutrophil extracellular traps (NETs) evolved as a unique effector mechanism contributing to resistance against infection that can also promote tissue damage in inflammatory conditions. Malaria infection can trigger NET release, but the mechanisms and consequences of NET formation in this context remain poorly characterized. Here we show that patients suffering from severe malaria had increased amounts of circulating DNA and increased neutrophil elastase (NE) levels in plasma. We used cultured erythrocytes and isolated human neutrophils to show that Plasmodium-infected red blood cells release macrophage migration inhibitory factor (MIF), which in turn caused NET formation by neutrophils in a mechanism dependent on the C-X-C chemokine receptor type 4 (CXCR4). NET production was dependent on histone citrullination by peptidyl arginine deiminase-4 (PAD4) and independent of reactive oxygen species (ROS), myeloperoxidase (MPO) or NE. In vitro, NETs functioned to restrain parasite dissemination in a mechanism dependent on MPO and NE activities. Finally, C57/B6 mice infected with P. berghei ANKA, a well-established model of cerebral malaria, presented high amounts of circulating DNA, while treatment with DNAse increased parasitemia and accelerated mortality, indicating a role for NETs in resistance against Plasmodium infection.

Assuntos

Eritrócitos/imunologia , Armadilhas Extracelulares/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Malária/imunologia , Neutrófilos/imunologia , Plasmodium/imunologia , Receptores CXCR4/metabolismo , Animais , Eritrócitos/metabolismo , Eritrócitos/parasitologia , Armadilhas Extracelulares/metabolismo , Armadilhas Extracelulares/parasitologia , Humanos , Malária/metabolismo , Malária/parasitologia , Malária/patologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/metabolismo , Neutrófilos/parasitologia , Parasitemia/imunologia , Parasitemia/metabolismo , Parasitemia/parasitologia , Parasitemia/patologia

RESUMO

Dramatic changes in the environment and human lifestyle have been associated with the rise of various chronic complex diseases, such as inflammatory bowel disease (IBD). A dysbiotic gut microbiota has been proposed as a crucial pathogenic element, contributing to immune imbalances and fostering a proinflammatory milieu, which may be associated with disease relapses or even the initiation of IBD. In addition to representing important regulators of the mucosal immunity and the composition of the gut microbiota, food components have been shown to be potential environmental triggers of epigenetic modifications. In the context of chronic intestinal inflammation, dietary habits and specific food components have been implicated as important modulators of epigenetic mechanisms, including DNA methylation, which may predispose a person to the increased risk of the initiation and evolution of IBD. This review provides novel insights about how dietary factors may interact with the intestinal mucosa and modulate immune homeostasis by shaping the intestinal ecosystem, as well as the potential influence of diet in the etiopathogenesis and management of IBD.

Assuntos

Dieta/efeitos adversos , Comportamento Alimentar , Doenças Inflamatórias Intestinais/etiologia , Estilo de Vida , Animais , Dieta Saudável , Disbiose , Epigênese Genética , Microbioma Gastrointestinal , Interação Gene-Ambiente , Interações Hospedeiro-Patógeno , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Intestinos/microbiologia , Prognóstico , Fatores de Proteção , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco

RESUMO

The purpose of the present study was to investigate the geographical distribution and time trends of the incidence and lethality of esophageal cancer (EC) in Brazil. The present study conducted an ecological study of EC using records from January 2005 to December 2015 in the Health Informatics Department of the Brazilian Ministry of Health (DATASUS) registry. In addition to demographical data on the population, EC incidence and lethality rates were estimated from hospitalizations and in-hospital mortalities and were adjusted by total available hospital beds. The adjusted EC rates per 100,000 increased from 9.1 in 2005 to 12.1 in 2015. The prevalence among males increased from 69 to 78%, while the female rates remained stable over the same period. Although EC was the most common in South and Southeast Brazil, the rates increased proportionately more in the other regions of the country, especially among males. Geographical analysis revealed higher rates of EC in more urbanized areas, with a coast-to-inland gradient. While rates increased in people older than 50 years, they decreased among people below this age. However, the lethality rates remained stable and high during the study period, overlapping with hospital admission rates. The recent increasing trend in the EC incidence, with shifts from the south towards the north and from more urbanized towards rural areas, suggests that environmental factors are crucial in EC pathogenesis. The concentration of EC in South Brazil may reflect the presence of major environmental factors in association with a possible genetic predisposition. The unchanging high mortality associated with EC in the rapidly aging population suggests that EC will continue to impose a significant social and economic burden in the future.

RESUMO

Background and aims: Mice orally infected with T. gondii develop Crohn's disease (CD)-like enteritis associated with severe mucosal damage and a systemic inflammatory response, resulting in high morbidity and mortality. Previously, helminthic infections have shown therapeutic potential in experimental colitis. However, the role of S. mansoni in T. gondii-induced CD-like enteritis has not been elucidated. Our study investigated the mechanisms underlying T. gondii-induced ileitis and the potential therapeutic effect of S. mansoni coinfection. Methods: C57BL/6 mice were infected by subcutaneous injection of cercariae of the BH strain of S. mansoni, and 7-9 weeks later, they were orally infected with cysts of the ME49 strain of T. gondii. After euthanasia, the ileum was removed for histopathological analysis; staining for goblet cells; immunohistochemistry characterizing mononuclear cells, lysozyme expression, apoptotic cells, and intracellular pathway activation; and measuring gene expression levels by real-time PCR. Cytokine concentrations were measured in the serial serum samples and culture supernatants of the ileal explants, in addition to myeloperoxidase (MPO) activity. Results:T. gondii-monoinfected mice presented dense inflammatory cell infiltrates and ulcerations in the terminal ileum, with abundant cell extrusion, apoptotic bodies, and necrosis; these effects were absent in S. mansoni-infected or coinfected animals. Coinfection preserved goblet cells and Paneth cells, remarkably depleted in T. gondii-infected mice. Densities of CD4- and CD11b-positive cells were increased in T. gondii- compared to S. mansoni-infected mice and controls. MPO was significantly increased among T. gondii-mice, while attenuated in coinfected animals. In T. gondii-infected mice, the culture supernatants of the explants showed increased concentrations of TNF-alpha, IFN-gamma, and IL-17, and the ileal tissue revealed increased expression of the mRNA transcripts for IL-1 beta, NOS2, HMOX1, MMP3, and MMP9 and activation of NF-kappa B and p38 MAPK signaling, all of which were counterregulated by S. mansoni coinfection. Conclusion:S. mansoni coinfection attenuates T. gondii-induced ileitis by preserving mucosal integrity and downregulating the local inflammatory response based on the activation of NF-kappa B and MAPK. The protective function of prior S. mansoni infection suggests the involvement of innate immune mechanisms and supports a conceptually new approach to the treatment of chronic inflammatory diseases, including CD.

Assuntos

Coinfecção/imunologia , Ileíte/prevenção & controle , Mucosa Intestinal/fisiopatologia , Esquistossomose mansoni/imunologia , Terapia com Helmintos , Toxoplasmose Animal/terapia , Animais , Apoptose , Doença de Crohn/terapia , Citocinas/sangue , Modelos Animais de Doenças , Regulação para Baixo , Epitélio/fisiologia , Perfilação da Expressão Gênica , Ileíte/etiologia , Ileíte/imunologia , Ileíte/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Peroxidase/sangue , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Toxoplasmose Animal/complicações , Toxoplasmose Animal/imunologia

RESUMO

BACKGROUND AND AIMS: To compare tuberculin skin test (TST) and interferon gamma release assay (IGRA) in the screening of LTBI among patients with inflammatory bowel disease (IBD) in an endemic area for tuberculosis, to evaluate the need for repeating tests during anti-TNFα, therapy, and to check whether the results may be affected by immunosuppression. METHODS: A cross-sectional study of 110 IBD patients and 64 controls was conducted in Rio de Janeiro, Brazil. The TST was administered after the Quantiferon(®)-TB Gold In-tube test was performed. RESULTS: TST and IGRA agreement was poor regarding diagnosis (kappa: control = 0.318; UC = 0.202; and CD = - 0.093), anti-TNFα therapy (kappa: with anti-TNFα = 0.150; w/o anti-TNFα = - 0.123), and immunosuppressive therapy (IST) (kappa: with IS = - 0.088; w/o IS = 0.146). Indeterminate IGRA was reported in four CD patients on IST. Follow-up tests after anti-TNFα identified conversion in 8.62% using TST and 20.0% using IGRA. Considering IGRA as a criterion standard, TST showed low sensitivity (19.05%) and positive predictive value (PPV) (21.05%). LTBI detection remarkably improved when IGRA was added to TST (sensitivity of 80.95% and PPV of 53.13%). Results were particularly relevant among CD patients where rates started from zero to reach sensitivity and PPV of more than 60%. CONCLUSION: IGRA alone was more effective to detect LTBI than TST alone and had an overall remarkable added value as an add-on sequential test, particularly in CD patients. While cost-effectiveness of these strategies remains to be evaluated, IGRA appears to be justified in CD prior to and during anti-TNFα therapy, where tuberculosis is endemic.

Assuntos

Produtos Biológicos/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Testes de Liberação de Interferon-gama , Tuberculose Latente/diagnóstico , Teste Tuberculínico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Produtos Biológicos/efeitos adversos , Brasil , Estudos Transversais , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/imunologia , Tuberculose Latente/imunologia , Tuberculose Latente/microbiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Risco , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem

RESUMO

BACKGROUND AND AIMS: Magnetic resonance enterography (MRE) has become an important modality of radiological imaging in the evaluation of Crohn's disease (CD). The aim of this study was to investigate the impact of MRE in the assessment of disease activity and abdominal complications and in the making of therapeutic decisions for patients with CD. METHODS: In a cross-sectional retrospective study, we selected 74 patients with CD who underwent MRE and ileocolonoscopy with an interval between the two exams of up to 30 days between January 2011 and December 2017. We assessed the parameters of the images obtained by MRE and investigated the agreement with the level of disease activity and complications determined by a clinical evaluation, inflammatory biomarkers, and endoscopy, as well as the resulting changes in medical and surgical management. RESULTS: Changes in medical management were detected in 41.9% of patients. Significant changes in medical decisions were observed in individuals with a purely penetrating (P = .012) or a mixed (P = .024) MRE pattern. Patients with normal MRE patterns had a correlation with unchanged medical decisions (P = .001). There were statistically significant agreements between the absence of inflammatory criteria on MRE and remission according to the Harvey and Bradshaw index (HBI) (P = .037), the presence of inflammatory criteria on MRE and positive results for calprotectin (P = .005), and penetrating criteria on MRE and the scoring endoscopic system for Crohn's disease (SES-CD), indicating active disease (P = .048). Finally, there was significant agreement between the presence of fibrostenotic criteria and a long disease duration (P = .027). CONCLUSION: MRE discloses disease activity and complications not apparent with other modalities and results in changes in therapeutic decisions. In addition to being used for diagnosis, MRE should be routinely used in the follow-up of CD patients.